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Research Interests:
Research Synopsis:Our laboratory is interested in the molecular neuropharmacology of dopamine neurotransmission, with a specific focus on molecular drug design of dopamine receptor ligands. Classical pharmacology has divided dopamine receptors into two major families called D1 and D2. It is now known that two genes code for D1-like receptors (D1 and D5) and three for D2-like receptors (D2, D3, D4). We have several research goals: 1) to understand the structural basis that causes ligands to recognize and activate dopamine receptors (see Figure 1); 2) to understand why some ligands cause differential activation of signaling pathways linked to a single receptor (termed “functional selectivity”; see Figure 2 and brief review); and 3) to understand how molecular properties affect the actions of ligands in vivo, and to design drugs with novel bifunctional mechansism of action (see Figure 3); 4) to determine some of the genetic-environmental interactions that result in increased risk of Parkinson’s disease. During the past years, we have made several interesting findings with respect to these goals. As is shown in Figure 4, we have utilized computerized molecular modeling to refine a model of the D1 receptor recognition site that has been shown to predict the pharmacological activity of totally novel compounds. This model defines the spatial organization of aspects of the receptor that are important for high affinity drugs that are full agonists. Indeed, two compounds that we have discovered are currently in early clinical testin and late preclinical testing, respectively, for treatment of both Parkinson's disease and cognitive deficits in several CNS disorders. Our current efforts are to determine which specific amino acid residues of the receptor are involved in binding to ligands, and which play a role in functionally selective activation. How this might occur is shown in Figure 5. Many of the ligands developed as research tools have shown promise as drugs, and we do preliminary testing in various animal models, and also participate in the design of clinical studies. Recent Publications:
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